For decades, only protein encoding RNAs were thought to be involved in mediating cell functions. However, researchers have recently discovered that RNAs that do not encode proteins, such as micro ribonucleic acids (microRNAs) and long noncoding RNAs (lncRNAs), are also involved in the regulation of cellular processes. It is particularly striking to note that, although approximately 70% of genomic DNA is transcribed, only ˜1.2% of genomic transcripts have been found to encode proteins (Gutschner et al., RNA Biol, 9: 703-19, 2012).
To date, thousands of lncRNA have been discovered in cells, but the function of only a very small percentage (around 1%) of these lncRNAs has been characterized (Amaral et al., Nucleic Acids Res, 39:D146-51, 2011; Wilusz et al., Genes Develop. 23:1494-1504, 2009). Interestingly, of those lncRNA that have been studied, many have been shown to play important roles in the regulation of gene expression, and roles for lncRNA as mediators of oncogenic and tumour suppressive functions have been identified in pervasive cancer types, including breast and prostate cancers.
The mechanisms by which lncRNA are thought to modulate the expression of genes are multiple and diverse. One way in which nuclear-localized lncRNAs have been shown to act is in the control of gene expression. To do this, these lnRNAs guide epigenetic factors to gene regulatory sites in the genome. The lncRNA HOTAIR has been shown to work in cooperation with and recruit epigenetic factors to regulate programs of gene expression, and HOTAIR is involved processes that promote malignancy in cancers, including colorectal and breast cancers.
SATB1 (Dickinson et al., Cell, 70(4):631-45, 1992) is a nuclear protein that acts to regulate programs of gene expression through remodeling of the three-dimensional organization of the genome and epigenetic status of chromatin at a large number of target genomic loci. SATB1 is further described in U.S. Pat. No. 5,652,340 and antibodies made thereto are described in U.S. Pat. No. 5,869,621, which are hereby incorporated by reference.
SATB1 exhibits unique patterns of activity in the nuclei of aggressive breast cancer cells, and high levels of SATB1 expression directly correlate with a poor prognosis among breast cancer patients (Han et al., Nature, 452:187-193, 2008; Kohwi-Shigematsu et al., Seminars in Cancer Biology, 23:72-79, 2013; WO 2007/075206). In aggressive breast cancer cells, SATB1 reprograms the gene expression profile in order to promote cancer metastasis, and the knockdown of SATB1 expression in these cells blocks their tumorigenic and metastatic potential. Conversely, the ectopic expression of SATB1 in non-aggressive breast cancer cells increases their tumorigenic and metastatic potential. However, the mechanisms that operate in aggressive breast cancer to drive SATB1 expression or to guide SATB1 to its target gene loci are not yet known. Also, as a protein with other functions in multiple cell and tissue types, it is important to understand the mechanisms that are involved in directing the activities of SATB1 that increase the tumorigenic and, most importantly, the metastatic potential of breast cancers.
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